Glucose would control the contractions of the intestine involved in digestion, and even its own absorption, via mechanisms that involve the enteric nervous system. By describing these processes and studying their dysfunctions in diabetic mice, Toulouse researchers have just identified a modulation pathway that could be used to better control this metabolic disease.
In a normal situation, the ingestion of food is followed by an increase in the contraction of the intestine. Information is transmitted to the brain by the nervous system that controls the digestive system – the enteric nervous system. At the central level, certain mediators, such as nitric oxide (NO) produced by the hypothalamus, will then act to control and then normalize glycaemia, that is to say the quantity of sugar available in the blood. At the same time, the intestinal neurons also produce NO which participates in this regulation. But in diabetic mice and humans, after a meal, the hypermotricity of the intestine is exacerbated and the intestinal absorption of glucose is abnormally high. The control of glycaemia then escapes the classic mechanisms linked to the action of NO: the glucose remains in high quantity in the blood, and the peripheral tissues which use it as an energy source are less able to absorb it. A vicious circle sets in, harmful to the body’s glycemic balance.
The gut-brain axis that allows the digestive system and central nervous system to interact plays an obvious role in the development and maintenance of diabetes, but all the mechanisms remain to be precisely determined. Claude Knauf* and his team are working precisely to describe how this axis intervenes in the regulation of blood glucose, in normal or pathological situations. For several years, they have developed and confirmed a new concept, that of enterosyns: “These are molecules that can alter the functioning of the gut-brain axis by interacting with the enteric nervous systemsays the researcher. These are hormones, neurotransmittersof nutrientsbacteria or metabolites bacteria that are able to control the contractions of the intestine and thus modulate the messages sent to the brain. The objective of our laboratory is therefore to identify among these molecules those which would be able to slow intestinal motility to improve diabetes control. »
Targeting the GLUT2 pathway
Their work led them to look into the impact of glucose itself: what effect does it have precisely on intestinal motility and by what mechanisms? Through experiments carried out in vitro and in mice, the researchers showed that glucose stimulates intestinal contractions during a meal, by interacting with two intestinal glucose transporters: SGLT-1 and GLUT2. When the meal is abnormally rich, the level of expression of the genes coding for these two transporters increases and therefore logically increases blood sugar. In diabetics, this mechanism is so exacerbated that it leads to a plateau beyond which glucose no longer has any additional effect on the motility of the intestine.
At the same time, the team described a direct link between the concentration of glucose in the blood and the reduction in the release of NO by the enteric nervous system, under the effect of GLUT2. Then, using a GLUT2 inhibitor, phloretin, she observed that the mechanism was reversible: thanks to this inhibitor, it is possible to reduce the effect of glucose on intestinal contractions, in normal mice as well as in diabetic animals. . For Claude Knauf, “ targeting this transporter could therefore be particularly relevant to better control glucose absorption in type 2 diabetics: this strategy could lead to restoring a functional gut-brain axis ».
Before considering such an approach more concretely, the researcher now wishes to study the repercussions of the mechanisms described here at the cerebral level. ” We have already identified the impact of several enterosyns – such as apelin, galanin, or certain prebiotics comme l’oligofructose – on cerebral NO level and improvement of diabetic status. We would now like to find enterosyns capable of interacting with the signaling pathway triggered by GLUT2. Such molecules would constitute as many alternatives or complementary approaches to those currently offered to people who suffer from type 2 diabetes. concludes the scientist.
* unit 1220 Inserm/INRAE/Toulouse III – Paul-Sabatier University/National Veterinary School, Digestive Health Research Institute, Physiopathology of the gut-brain axis teamToulouse
Source : E. Wemelle et coll. Glucose Stimulates Gut Motility in Fasted and Fed Conditions : Potential Involvement of a Nitric Oxide Pathway. Nutrientsonline edition 23 May 2022. DOI: 10.3390/nu14102176.